The heart relies heavily on oxidation of fatty acids for
energy production. However, excess storage of fatty acids as triglycerides,
within heart muscle cells, frequently observed in patients with obesity and
diabetes, is often associated with cardiac dysfunction. The question remained:
was this cause and effect? Now a team of investigators shows that baseline
heart function “showed moderate, but significant improvement” in mouse models
that overproduce an enzyme that breaks down these triglycerides, says principal
investigator Jason Dyck, of the University of Alberta, Edmonton. The research
is published in the February Molecular
and Cellular Biology.

The investigators showed further that mice that overproduce
the enzyme “were able to run 20% longer than the controls when subjected to a
treadmill test,” says first author Petra Kienesberger, of the University of
Alberta.

Then, in experiments in which mouse models were surgically
constructed to mimic hypertension, the researchers showed that “overproduction
of the enzyme protects from the development of cardiac/contractile dysfunction
under this pathological condition,” says Kienesberger.

“Together, these data demonstrate for the first time that
decreased myocardial triglyceride accumulation plays a role in regulating
cardiac function at baseline as well as an important protective role in
preventing cardiac dysfunction in response to a severe pressure overload, as
observed with hypertension,” says Dyck.

“These findings are highly relevant to basic and clinical
research,” says Kienesberger. “They suggest that regulation of cardiac
triglyceride content and breakdown plays a central role in mediating cardiac
function, and that pharmacological modification of cardiac [enzymatic] activity
[to break down triglyceride] could be used as therapy to improve contractile
function of the diseased heart. However, it remains to be tested whether
reducing triglycerides is also beneficial in obesity and diabetes. This
concept… opens new avenues of research not previously identified.”

The research was enabled only recently by new genetic tools
that specifically target cardiac triglycerides and by a novel mouse model, in
which triglyceride could be reduced by boosting the enzyme responsible for
breaking it down, says Kienesberger.